Triethylamine → 4-(8-Aza-bicyclo[3.2.1]oct-3-ylamino)-6-chloro-1-(2,2,2-trifluoro-ethyl)-1H-quinazolin-2-One

HRID 897262Notes

Reaction equation

HRID 897262 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[NH:6][C:5]2=O.C(N(CC)CC)C.C(OC([N:31]1[CH:36]2[CH2:37][CH2:38][CH:32]1[CH2:33][CH:34]([NH2:39])[CH2:35]2)=O)C>P(Cl)(Cl)(Cl)=O.CN(C=O)C>[CH:32]12[NH:31][CH:36]([CH2:37][CH2:38]1)[CH2:35][CH:34]([NH:39][C:5]1[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[N:6]=1)[CH2:33]2

Participants

6

Reactant 3

HCID 8471Triethylamine2×HCID 18507024Ethyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylateHCID 22347996HCID 22347996, compound

Product 1

HCID 223480694-(8-Aza-bicyclo[3.2.1]oct-3-ylamino)-6-chloro-1-(2,2,2-trifluoro-ethyl)-1H-quinazolin-2-One

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 24813Phosphorus oxychlorideSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 6-chloro-1-(2,2,2-trifluoro-ethyl)-1H-quinazoline-2,4-dione (1.10 g, 3.97 mmol) in phosphorous oxychloride (15 mL) was added 1 mL triethylamine. The reaction was heated to 100° C., stirred for 4 hrs and concentrated. The crude residue was dissolved in chloroform, washed with 1 N aq sodium hydroxide, dried over Na2SO4, filtered, and concentrated. To a solution of the crude residue in DMF (50 mL), was added triethylamine (1 mL) and 3-amino-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (1.0 g, 5.50 mmol). The solution was heated to 50° C. and stirred for 12 hrs. The reaction was partitioned between ethyl acetate and water and the organic phase was washed an additional 2× with water and brine, dried over Na2SO4, filtered, and concentrated. The resultant yellow foam was treated with HBr solution (6 mL, 30 weight % in AcOH) in a pressure vessel at 100° C. After 4 hrs the solution was cooled and concentrated (1.1 g). 1H NMR (300 MHz, CD3OD) δ ppm 2.20 (m, 8H), 4.16 (m, 2H), 4.65 (m, 1H), 5.04 (q, J=8.6 Hz, 2H), 7.62 (d, J=9.0 Hz, 1H), 7.83 (dd, J=2.2, 9.0 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H); MS (ESI+Q1MS) m/z 388 [M+2H]+

Workup

  1. concentrationconcentrated
  2. dissolutionThe crude residue was dissolved in chloroform
  3. washwashed with 1 N aq sodium hydroxide
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. temperatureThe solution was heated to 50° C.
  8. stirringstirred for 12 hrs
  9. customThe reaction was partitioned between ethyl acetate and water
  10. washthe organic phase was washed an additional 2× with water and brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. additionThe resultant yellow foam was treated with HBr solution (6 mL, 30 weight % in AcOH) in a pressure vessel at 100° C
  15. temperatureAfter 4 hrs the solution was cooled
  16. concentrationconcentrated (1.1 g)

Sources & evidence

ORD record
ord-489bcac906d2416486e4311c33ca05d9
Source dataset
uspto-grants-2005_07
Patent number
US06921821B2

Reaction notes

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